US20170354621A1 - Sulfonamide pharmaceutical composition - Google Patents
Sulfonamide pharmaceutical composition Download PDFInfo
- Publication number
- US20170354621A1 US20170354621A1 US15/541,776 US201615541776A US2017354621A1 US 20170354621 A1 US20170354621 A1 US 20170354621A1 US 201615541776 A US201615541776 A US 201615541776A US 2017354621 A1 US2017354621 A1 US 2017354621A1
- Authority
- US
- United States
- Prior art keywords
- solution
- sulfonamide
- pharmaceutical composition
- raw materials
- stirring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- UAEPNZWRGJTJPN-UHFFFAOYSA-N CC1CCCCC1 Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 0 *NS(=O)(=O)C1=C(C)C=CC=C1.*NS(=O)(=O)C1=CC=C(C)C=C1 Chemical compound *NS(=O)(=O)C1=C(C)C=CC=C1.*NS(=O)(=O)C1=CC=C(C)C=C1 0.000 description 3
- YYDNBUBMBZRNQQ-UHFFFAOYSA-N CC1=CC=C(S(C)(=O)=O)C=C1 Chemical compound CC1=CC=C(S(C)(=O)=O)C=C1 YYDNBUBMBZRNQQ-UHFFFAOYSA-N 0.000 description 3
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This invention relates to a sulfonamide pharmaceutical composition, and their preparation and use in the pharmaceutical industry.
- Cancer is a common disease in the world today. Most cancers are diagnosed at late stage and the cure rate is low. Most of the current anticancer drugs have toxic side effects including hair loss, vomiting, decrease of white blood cell count, bone marrow suppression, and decrease in immune system function. The major reason is that these drugs act on part of the cell metabolic cycle, and they do not selectively target cancer cells as opposed to healthy cells. When they kill cancer cells, they also damage healthy cells, especially those healthy cells that are undergoing rapid metabolism.
- Sulfonamide compounds have been clinically used as an antimicrobial for decades. Today, they are still one of the most commonly used antimicrobials, second only to antibiotics because of their broad antibacterial spectrum, stability, ease of use, and low price. As more in-depth studies are conducted, researchers have found that sulfonamide compounds have a wider range of biological activities, including its diuretic effect, anti-thyroid effect, anti-diabetic effect, anti-hypoglycemic effect, and its ability to treat cataract. In recent years, a large number of sulfonamide compounds with anti-tumor activity have been reported, and many among them have entered clinical trials. These compounds act on different molecular targets and exhibit significant biological activity. Some compounds exhibit high selectivity and specificity for different targets.
- the mechanisms for the actions of these sulfonamide compounds are diverse, including disrupting tubulin polymerization, blocking normal cell cycle, inhibiting carbonic anhydrase, inhibiting folic acid dependent enzymes, inhibiting methionine aminopeptidase and histone deacetylase, and inhibiting vascular endothelial cell growth factor and so on.
- Chinese Patent ZL97108988.4 disclosed the formulation and method to prepare injections of sulfonamide compounds.
- the compounds include:
- sulfonamide compounds are selected from:
- Said sulfonamide compound 10% ⁇ 80% PEG-400 10% ⁇ 60% 1,2-propanediol 5% ⁇ 30%
- p-Toluenesulfonic acid 1% ⁇ 15% Dimethyl sulfoxide 0% ⁇ 20%
- the present invention solves the problems of low solubility and ease of crystallization associated with known injection formulations by improving the formulation and method to prepare injections of sulfonamide compounds. Comparative toxicity test also shows that the present formulation is less toxic and safer for clinical use.
- the goal of this invention is to provide an injection formulation comprising a sulfonamide compound, made with the following raw materials:
- PEG-400 polyethylene glycol-400
- 1,2-propanediol, sebacic acid, 2-ethyl-1,3-hexanediol, dimethyl sulfoxide and ethanol only dimethyl sulfoxide and ethanol are dispensable, others are required.
- the sulfonamide compound is selected from one, or a mixture of two or more, at any ratio, of the following:
- the sulfonamide compound is selected from:
- the injection formulation of the present invention is prepared from the following raw materials:
- injection formulation of this invention is prepared from the following raw materials:
- the present invention improves upon the known injection formulations by removing suberic acid and adding the solubilizer 2-ethyl-1,3-hexanediol.
- the combination of PEG-400, 2-ethyl-1,3-hexanediol, and 1,2-propanediol can decrease the amount of 1,2-propanediol in the injection formulation, thereby decreasing irritation at the injection site.
- Another goal of this invention is to provide a method to prepare the injection.
- the preparation of the injection of this invention comprises the following steps:
- the present invention is an improvement on the basis of the prior art (CN1073415C). As shown in the above table, the formulation of the present invention made the following improvements as compared to the formulation disclosed in Example 2 of the Chinese patent CN1073415C:
- this invention solved a range of issues associated with the known formulation such as low stability.
- Example 1 Example 2 p-Toluenesulfonamide 30% 40% PEG-400 33.5% 40% 1,2-propanediol 16.4% 10% Suberic acid 8.2% 3% p-Toluenesulfonic acid 3.7% 2% Dimethyl sulfoxide 6.7% 3% Ethanol 1.5% 2% Stability Stored at Stored at 4° C. ⁇ 2° C. for 4° C. ⁇ 2° C. for 10 days, 10 days, crystals crystals precipitated precipitated LD50 12.54 mg/kg 11.30 mg/kg
- Results show that, although all raw materials dissolved in Formula I and II, the time taken is relatively long while for Formula III-VI, raw materials dissolved faster and the final solution is clear and transparent.
- the present invention is further compared with existing pharmaceutical injections.
- Example 1 Three samples were taken from each of Example 1, Example 5, Example 6, and Example 7 (i.e., Formulation III-VI) of the present invention (Labelled as Samples A-D), and three samples were taken from self-prepared Example 2 from Patent CN1073415C (Labelled as Sample E). All samples were stored at 4° C. ⁇ 2° C. for 10 days and samples were observed at Day 0, Day 5, and Day 5 for crystal precipitation. Results are shown in Table 2:
- Formulations III-VI of the present invention showed a significant increase in stability at 4° C. compared to self-prepared CN 1073415C Example 2.
- the solution is clear and transparent after 10-day storage, and no crystal precipitated.
- Example 1 Samples were taken from Example 1, Example 5, Example 6 and Example 7 (i.e., Formulation III-VI) of the present invention (Labelled as Samples A-D), and self-prepared CN 1073415 C Example 2 (Labelled as Sample E), and stored at 40° C.+2° C., 75% ⁇ 5% RH. Relevant properties were assessed and results are shown in the below table:
- Formulations III-IV of the present invention were significantly more stable after storage at 40° C. ⁇ 2° C., 75% ⁇ 5% RH for 6 months compared to CH1073415C Example 2.
- the growth rates of single largest impurity and total impurities were slower, and there were fewer impurities.
- the degradation rates of the raw materials were also slower and there was less degradation for Formulations III-IV.
- the purpose of adding anhydrous ethanol in this formulation is to control the total volume of the final solution, and further control the total drug content in the formulation. Therefore, the amount of anhydrous ethanol to be added in Step 4 should be slightly less than the prescription amount.
- Example 1 of the p-toluenesulfonamide injection was compared with CN 1073415 C Example 2 by administering a single intravenous injection at the tail vein for comparative toxicity test. Results are shown below:
- Example 1 Animal death rate is lower for Example 1.
- LD50 of the drug was increased by 60% (P ⁇ 0.01), significantly reducing the toxicity of the injection.
- Example 1 of the present invention was tested on animals.
- Table 2 shows the effect of intramuscular injection of Example 1 on the development of lung cancer in mice.
- Example 1 Effect of intramuscular injection of Example 1 on lung cancer development in mice No. of Body Average weight Dosage subjects weight of tumor Tumor-inhibiting Group Treatment (/kg/d ⁇ 10 d) Start End Start End (X ⁇ SD) (g) rate (%) P value* 1 NS(contnol) 2.0 ml 11 11 20.7 27.9 3.52 ⁇ 0.62 0.0 >0.05 Solvent 2.0 ml 11 11 20.5 25.1 2.91 ⁇ 0.58 17.3 ⁇ 0.01 (control) CTX 18.0 ml 11 11 20.8 25.0 1.82 ⁇ 0.41 48.3 ⁇ 0.01 Example 1 0.5 ml 11 11 21.9 25.4 1.81 ⁇ 0.25 48.6 ⁇ 0.01 Example 1 1.0 ml 11 11 21.3 25.2 1.46 ⁇ 0.74 58.5 ⁇ 0.01 Example 1 2.0 ml 11 11 20.2 24.0 1.25 ⁇ 0.72 64.5 ⁇ 0.01 2 NS(control) 2.0 ml 11 11 20.4 27.7 2.49 ⁇ 0.58 0.0 >0.05
- Example 1 injection Single-arm clinical trial of Example 1 injection (PTS injection) for local intra-tumoral injection in patients with severe airway obstruction due to central type lung cancer.
- Subject statistics based on their lung cancer stage 46 cases in IV phase, 22 cases in stage IIIb, 4 cases in stage IIIa. Subject statistics based on the location of tumor, 6 cases of airway, 28 cases of left main bronchus, 30 cases of right main bronchus, and 8 cases of right intermediate bronchus.
- Major efficacy index objective response rate of intraluminal target lesion-according to RECIST: based on CT assessment, the objective response rate was 68.08% within 7 days from the last treatment, and 48.61% after 30 days from the exit period, respectively.
- Major efficacy index objective response rate of intraluminal target lesion-according to WHO standard: based on CT assessment, the objective response rate of intraluminal target lesion was 77.78% within 7 days from the last treatment, and 54.17% after 30 days from the exit period.
- Major efficacy index improvement rate on luminal tumor blockage, applying CT assessment, the improvement rate for obstruction due to luminal tumor is 70.45% within 7 days from the last treatment, and 70.47% after 30 days from the exit period.
- Clinical benefit index Compared with the baseline, the pulmonary function index FEV1 showed statistically significant improvement within 7 days after the last administration, with a rate of improvement of 34.72% and 18.06% at 30 days after the exit period; the total re-expansion rate for patients with atelectasis across different lobes was 44.44% (20/45). Arranged by the location with a descending re-expansion rate is as follows: 50.00% for the right middle lobe, 43.75% for the left lung, 42.11% for the left lower lobe, 38.46% for the right lower lobe, 35.00% for the left tongue lobe, and 25.00% for the right upper lobe.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510005995.5A CN104473914B (zh) | 2015-01-06 | 2015-01-06 | 一种磺酰胺类药物组合物 |
CN2015100059955 | 2015-01-06 | ||
PCT/CN2016/070015 WO2016110225A1 (zh) | 2015-01-06 | 2016-01-04 | 一种磺酰胺类药物组合物 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2016/070015 A-371-Of-International WO2016110225A1 (zh) | 2015-01-06 | 2016-01-04 | 一种磺酰胺类药物组合物 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/377,428 Continuation US11040020B2 (en) | 2015-01-06 | 2019-04-08 | Sulfonamide pharmaceutical composition |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170354621A1 true US20170354621A1 (en) | 2017-12-14 |
Family
ID=52748619
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/541,776 Abandoned US20170354621A1 (en) | 2015-01-06 | 2016-01-04 | Sulfonamide pharmaceutical composition |
US16/377,428 Active 2036-02-08 US11040020B2 (en) | 2015-01-06 | 2019-04-08 | Sulfonamide pharmaceutical composition |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/377,428 Active 2036-02-08 US11040020B2 (en) | 2015-01-06 | 2019-04-08 | Sulfonamide pharmaceutical composition |
Country Status (11)
Country | Link |
---|---|
US (2) | US20170354621A1 (de) |
EP (1) | EP3243510B1 (de) |
JP (1) | JP6502507B2 (de) |
KR (1) | KR101949810B1 (de) |
CN (2) | CN104473914B (de) |
AU (1) | AU2016206154B2 (de) |
CA (1) | CA2972834C (de) |
MX (1) | MX2017008983A (de) |
RU (1) | RU2715700C2 (de) |
SG (1) | SG11201705543VA (de) |
WO (1) | WO2016110225A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230098310A1 (en) * | 2021-09-29 | 2023-03-30 | Gongwin Biopharm Co., Ltd | Methods for treating mast cell tumors |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104473914B (zh) * | 2015-01-06 | 2017-01-11 | 天津红日药业股份有限公司 | 一种磺酰胺类药物组合物 |
CN113368251A (zh) * | 2020-02-25 | 2021-09-10 | 上海和绎实业有限公司 | 一种组合溶剂及其制备方法和应用 |
US11752160B2 (en) * | 2020-09-24 | 2023-09-12 | Gongwin Biopharm Co., Ltd | Method for reducing fat by administering benzenesulfonamide compositions |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5891454A (en) * | 1997-03-28 | 1999-04-06 | Alexander Wu | Anti-cancer drug and special tumor necrotizing agent |
US5783705A (en) * | 1997-04-28 | 1998-07-21 | Texas Biotechnology Corporation | Process of preparing alkali metal salys of hydrophobic sulfonamides |
CN1073415C (zh) * | 1997-07-03 | 2001-10-24 | 吴宜庄 | 磺酰胺类化合物在制备抗癌药物中的应用 |
ATE267613T1 (de) * | 1998-03-05 | 2004-06-15 | Phares Pharm Res Nv | Arzneimittel und deren verwendung |
US6727287B2 (en) * | 2001-04-16 | 2004-04-27 | Pts International, Inc. | Toluene sulfonamide-containing anti-tumor composition and method of use thereof |
CN102389410A (zh) * | 2011-11-03 | 2012-03-28 | 黄漫翔 | 对-甲苯磺酰胺在制备癌症治疗药物中的应用 |
CN104473914B (zh) * | 2015-01-06 | 2017-01-11 | 天津红日药业股份有限公司 | 一种磺酰胺类药物组合物 |
-
2015
- 2015-01-06 CN CN201510005995.5A patent/CN104473914B/zh active Active
-
2016
- 2016-01-04 US US15/541,776 patent/US20170354621A1/en not_active Abandoned
- 2016-01-04 JP JP2017536587A patent/JP6502507B2/ja active Active
- 2016-01-04 MX MX2017008983A patent/MX2017008983A/es active IP Right Grant
- 2016-01-04 CA CA2972834A patent/CA2972834C/en active Active
- 2016-01-04 WO PCT/CN2016/070015 patent/WO2016110225A1/zh active Application Filing
- 2016-01-04 EP EP16734885.3A patent/EP3243510B1/de active Active
- 2016-01-04 SG SG11201705543VA patent/SG11201705543VA/en unknown
- 2016-01-04 CN CN201680005040.2A patent/CN107205974A/zh active Pending
- 2016-01-04 KR KR1020177018819A patent/KR101949810B1/ko active IP Right Grant
- 2016-01-04 RU RU2017126976A patent/RU2715700C2/ru active
- 2016-01-04 AU AU2016206154A patent/AU2016206154B2/en active Active
-
2019
- 2019-04-08 US US16/377,428 patent/US11040020B2/en active Active
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20230098310A1 (en) * | 2021-09-29 | 2023-03-30 | Gongwin Biopharm Co., Ltd | Methods for treating mast cell tumors |
Also Published As
Publication number | Publication date |
---|---|
JP6502507B2 (ja) | 2019-04-17 |
EP3243510B1 (de) | 2022-08-31 |
WO2016110225A1 (zh) | 2016-07-14 |
CN104473914B (zh) | 2017-01-11 |
US11040020B2 (en) | 2021-06-22 |
KR101949810B1 (ko) | 2019-02-19 |
EP3243510A4 (de) | 2018-08-08 |
MX2017008983A (es) | 2018-03-23 |
SG11201705543VA (en) | 2017-08-30 |
KR20170095926A (ko) | 2017-08-23 |
AU2016206154A1 (en) | 2017-07-27 |
CN104473914A (zh) | 2015-04-01 |
EP3243510A1 (de) | 2017-11-15 |
RU2017126976A3 (de) | 2019-08-22 |
US20190231721A1 (en) | 2019-08-01 |
CN107205974A (zh) | 2017-09-26 |
CA2972834A1 (en) | 2016-07-14 |
CA2972834C (en) | 2020-07-14 |
RU2017126976A (ru) | 2019-02-08 |
RU2715700C2 (ru) | 2020-03-03 |
JP2018501291A (ja) | 2018-01-18 |
AU2016206154B2 (en) | 2018-11-01 |
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